Multiple different biochemical defects have been identified in patients with genetic forms of extreme insulin resistance. These defects have included: (1) a decreased number of insulin receptors, (2) qualitatively abnormal insulin receptors which are impaired in their ability to couple insulin binding to insulin action, and (3) post-receptor defects in insulin action. We have applied the methods of cell biology to further define the nature of the receptor defects. Using cultured cells derived from insulin resistant patients with a decrease in receptor number, we have identified several different types of defects in the pathway of receptor biosynthesis. In a patient with qualitative abnormalities in insulin binding, we have obtained evidence suggesting that the patient is a genetic compound, having inherited two distinct mutant alleles which impair receptor function. In addition, with monocytes from a patient whose receptor-associated tyrosine kinase activity is defective, evidence has been obtained which suggests an abnormality in the molecular weight of the alpha-subunit of the insulin receptor. Most recently, in collaboration with Dr. Axel Ullrich, we have begun to apply recombinant DNA technology to determine whether there are mutations in the insulin receptor genes of these patients. In a related project, we have embarked upon studies to identify the cause of insulin resistance in an animal model of obesity and diabetes (the ob/ob mouse). Preliminary studies suggest that adenylate cyclase fat cells from ob/ob mice have abnormally increased sensitivity to adenosine.